4.1. Therapeutic indications

Asthma

Relvar Ellipta is indicated for the regular treatment of asthma in adults and adolescents aged 12 years and older where use of a combination medicinal product (long-acting beta2-agonist and inhaled corticosteroid) is appropriate:

• patients not adequately controlled with inhaled corticosteroids and 'as needed' inhaled short acting beta2-agonists.

• patients already adequately controlled on both inhaled corticosteroid and long-acting beta2-agonist.

4.2. Posology and method of administration

Posology

Asthma

Patients with asthma should be given the strength of Relvar Ellipta containing the appropriate fluticasone furoate (FF) dosage for the severity of their disease. Prescribers should be aware that in patients with asthma, fluticasone furoate (FF) 100 micrograms once daily is approximately equivalent to fluticasone propionate (FP) 250 micrograms twice daily, while FF 200 micrograms once daily is approximately equivalent to FP 500 micrograms twice daily.

Adults and adolescents aged 12 years and over

A starting dose of one inhalation of Relvar Ellipta 92/22 micrograms once daily should be considered for adults and adolescents 12 years and over who require a low to mid dose of inhaled corticosteroid in combination with a long-acting beta2-agonist. If patients are inadequately controlled on Relvar Ellipta 92/22 micrograms, the dose can be increased to 184/22 micrograms, which may provide additional improvement in asthma control.

Patients should be regularly reassessed by a healthcare professional so that the strength of fluticasone furoate/vilanterol they are receiving remains optimal and is only changed on medical advice. The dose should be titrated to the lowest dose at which effective control of symptoms is maintained.

Relvar Ellipta 184/22 micrograms should be considered for adults and adolescents 12 years and over who require a higher dose of inhaled corticosteroid in combination with a long-acting beta2-agonist.

Patients usually experience an improvement in lung function within 15 minutes of inhaling Relvar Ellipta.

However, the patient should be informed that regular daily usage is necessary to maintain control of asthma symptoms and that use should be continued even when asymptomatic.

If symptoms arise in the period between doses, an inhaled, short-acting beta2-agonist should be used for immediate relief.

The maximum recommended dose is Relvar Ellipta 184/22 micrograms once daily.

Children aged under 12 years

The safety and efficacy of Relvar Ellipta in children under 12 years of age have not been established in the indication for asthma.

Relvar Ellipta should not be used in children under 12 years of age. Currently available data are described in sections 5.1 and 5.2.

Special populations

Elderly

No dose adjustment is required in patients 65 years of age or older (see section 5.2).

Renal impairment

No dose adjustment is required in this population (see section 5.2).

Hepatic impairment

Studies in subjects with mild, moderate and severe hepatic impairment showed an increase in systemic exposure to fluticasone furoate (both Cmax and AUC) (see section 5.2).

Caution should be exercised when dosing patients with hepatic impairment who may be more at risk of systemic adverse reactions associated with corticosteroids.

For patients with moderate or severe hepatic impairment the maximum dose is 92/22 micrograms (see section 4.4).

Method of administration

Relvar Ellipta is for oral inhalation only.

It should be administered at the same time of the day, each day.

The final decision on evening or morning dosing should be left to the discretion of the physician.

After inhalation, patients should rinse their mouth with water without swallowing.

If a dose is missed the next dose should be taken at the usual time the next day.

If stored in a refrigerator, the inhaler should be allowed to return to room temperature for at least an hour before use.

When the inhaler is used for the first time, there is no need to check that it is working properly, and to prepare it for use in any special way. The step-by-step instructions should be followed.

The Ellipta inhaler is packaged in a tray containing a desiccant sachet, to reduce moisture. The desiccant sachet should be thrown away and it should not be opened, eaten or inhaled.

The patient should be advised to not open the tray until they are ready to inhale a dose.

When the inhaler is taken out of its tray, it will be in the 'closed' position. The “Discard by” date should be written on the inhaler label in the space provided. The “Discard by” date is 6 weeks from the date of opening the tray. After this date the inhaler should no longer be used. The tray can be discarded after first opening.

The step-by-step instructions shown below for the 30-dose Ellipta inhaler (30 day supply) also apply to the 14-dose Ellipta inhaler (14 day supply).

Instructions for use

1. Read this before you start

If the inhaler cover is opened and closed without inhaling the medicinal product, the dose will be lost. The lost dose will be securely held inside the inhaler, but it will no longer be available to be inhaled.

It is not possible to accidentally take extra medicinal product or a double dose in one inhalation.

2. Prepare a dose

Open the cover when ready to inhale a dose. The inhaler should not be shaken.

Slide the cover down until a 'click' is heard. The medicinal product is now ready to be inhaled.

The dose counter counts down by 1 to confirm. If the dose counter does not count down as the 'click' is heard, the inhaler will not deliver a dose and should be taken back to a pharmacist for advice.

3. How to inhale the medicinal product

The inhaler should be held away from the mouth breathing out as far as is comfortable, but not breathing out into the inhaler.

The mouthpiece should be placed between lips and the lips should be then closed firmly around it. The air vents should not be blocked with fingers during use.

• Inhale with one long, steady, deep breath in. The breath should be held as long as possible (at least 3-4 seconds).

• Remove the inhaler from the mouth.

• Breathe out slowly and gently.

The medicinal product may not be tasted or felt, even when using the inhaler correctly.

The mouthpiece of the inhaler may be cleaned using a dry tissue before closing the cover.

4. Close the inhaler and rinse your mouth

Slide the cover upwards as far as it will go to cover the mouthpiece.

Rinse your mouth with water after you have used the inhaler, do not swallow.

This will make it less likely to develop a sore mouth or throat as side effects.

4.3. Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Deterioration of disease

Fluticasone furoate/vilanterol should not be used to treat acute asthma symptoms, for which a short-acting bronchodilator is required. Increasing use of short-acting bronchodilators to relieve symptoms indicates deterioration of control and patients should be reviewed by a physician.

Patients should not stop therapy with fluticasone furoate/vilanterol in asthma, without physician supervision since symptoms may recur after discontinuation.

Asthma-related adverse events and exacerbations may occur during treatment with fluticasone furoate/vilanterol. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation of treatment with Relvar Ellipta.

Paradoxical bronchospasm

Paradoxical bronchospasm may occur with an immediate increase in wheezing after dosing. This should be treated immediately with a short-acting inhaled bronchodilator. Relvar Ellipta should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.

Cardiovascular effects

Cardiovascular effects, such as cardiac arrhythmias e.g. supraventricular tachycardia and extrasystoles may be seen with sympathomimetic medicinal products including Relvar Ellipta. In a placebo-controlled study in subjects with moderate COPD and a history of, or an increased risk of cardiovascular disease, there was no increase in the risk of cardiovascular events in patients receiving fluticasone furoate/vilanterol compared with placebo . However, fluticasone furoate/vilanterol should be used with caution in patients with severe cardiovascular disease or heart rhythm abnormalities, thyrotoxicosis, uncorrected hypokalaemia or patients predisposed to low levels of serum potassium.

Patients with hepatic impairment

For patients with moderate to severe hepatic impairment, the 92/22 micrograms dose should be used and patients should be monitored for systemic corticosteroid-related adverse reactions (see section 5.2).

Systemic corticosteroid effects

Systemic effects may occur with any inhaled corticosteroid, particularly at high doses prescribed for long periods. These effects are much less likely to occur than with oral corticosteroids. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, decrease in bone mineral density, growth retardation in children and adolescents, cataract and glaucoma and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children).

Fluticasone furoate/vilanterol should be administered with caution in patients with pulmonary tuberculosis or in patients with chronic or untreated infections.

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

Hyperglycaemia

There have been reports of increases in blood glucose levels in diabetic patients and this should be considered when prescribing to patients with a history of diabetes mellitus.

Pneumonia in patients with COPD

An increase in the incidence of pneumonia, including pneumonia requiring hospitalisation, has been observed in patients with COPD receiving inhaled corticosteroids. There is some evidence of an increased risk of pneumonia with increasing steroid dose but this has not been demonstrated conclusively across all studies.

There is no conclusive clinical evidence for intra-class differences in the magnitude of the pneumonia risk among inhaled corticosteroid products.

Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of such infections overlap with the symptoms of COPD exacerbations.

Risk factors for pneumonia in patients with COPD include current smoking, older age, low body mass index (BMI) and severe COPD.

Pneumonia in patients with asthma

The incidence of pneumonia in patients with asthma was common at the higher dose. The incidence of pneumonia in patients with asthma taking fluticasone furoate/vilanterol 184/22 micrograms was numerically higher compared with those receiving fluticasone furoate/vilanterol 92/22 micrograms or placebo (see section 4.8). No risk factors were identified.

Excipients

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the total lactase deficiency or glucose-galactose malabsorption should not use this medicinal product.

4.5. Interaction with other medicinal products and other forms of interaction

Clinically significant drug interactions mediated by fluticasone furoate/vilanterol at clinical doses are considered unlikely due to the low plasma concentrations achieved after inhaled dosing.

Interaction with beta-blockers

Beta2-adrenergic blockers may weaken or antagonise the effect of beta2-adrenergic agonists. Concurrent use of both non-selective and selective beta2-adrenergic blockers should be avoided unless there are compelling reasons for their use.

Interaction with CYP3A4 inhibitors

Fluticasone furoate and vilanterol are both rapidly cleared by extensive first pass metabolism mediated by the liver enzyme CYP3A4.

Caution is advised when co-administering with strong CYP 3A4 inhibitors (e.g. ketoconazole, ritonavir, cobicistat-containing products) as there is potential for increased systemic exposure to both fluticasone furoate and vilanterol. Co-administration should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid undesirable effects, in which case patients should be monitored for systemic corticosteroid undesirable effects. A repeat dose CYP3A4 drug interaction study was performed in healthy subjects with the fluticasone furoate/vilanterol combination (184/22 micrograms) and the strong CYP3A4 inhibitor ketoconazole (400 mg). Co-administration increased mean fluticasone furoate AUC(0‑24) and Cmax by 36% and 33%, respectively. The increase in fluticasone furoate exposure was associated with a 27% reduction in 0-24 hours weighted mean serum cortisol. Co-administration increased mean vilanterol AUC(0-t) and Cmax 65% and 22%, respectively. The increase in vilanterol exposure was not associated with an increase in beta2-agonist related systemic effects on heart rate, blood potassium or QTcF interval.

Interaction with P-glycoprotein inhibitors

Fluticasone furoate and vilanterol are both substrates of P-glycoprotein (P-gp). A clinical pharmacology study in healthy subjects with co-administered vilanterol and the potent P-gp and moderate CYP3A4 inhibitor verapamil did not show any significant effect on the pharmacokinetics of vilanterol. Clinical pharmacology studies with a specific P-gp inhibitor and fluticasone furoate have not been conducted.

Sympathomimetic medicinal products

Concomitant administration of other sympathomimetic medicinal products (alone or as part of combination therapy) may potentiate the adverse reactions of fluticasone furoate/vilanterol. Relvar Ellipta should not be used in conjunction with other long-acting beta2-adrenergic agonists or medicinal products containing long-acting beta2-adrenergic agonists.

Paediatric population

Interaction studies have only been performed in adults.

4.6. Fertility, pregnancy and lactation

Pregnancy

Studies in animals have shown reproductive toxicity at exposures which are not clinically relevant (see section 5.3). There are no or limited data from the use of fluticasone furoate and vilanterol trifenatate in pregnant women.

Administration of fluticasone furoate/vilanterol to pregnant women should only be considered if the expected benefit to the mother is greater than any possible risk to the foetus.

Breast-feeding

There is insufficient information on the excretion of fluticasone furoate or vilanterol trifenatate and/or metabolites in human milk. However, other corticosteroids and beta2-agonists are detected in human milk (see section 5.3). A risk to breastfed newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue fluticasone furoate/vilanterol therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

There are no fertility data in humans. Animal studies showed no effect of fluticasone furoate/vilanterol trifenatate on fertility (see section 5.3).

4.7. Effects on ability to drive and use machines

Fluticasone furoate or vilanterol has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

Summary of the safety profile

Data from large asthma and COPD clinical trials were used to determine the frequency of adverse reactions associated with fluticasone furoate/vilanterol. In the asthma clinical development programme a total of 7,034 patients were included in an integrated assessment of adverse reactions. In the COPD clinical development programme a total of 6,237 subjects were included in an integrated assessment of adverse reactions.

The most commonly reported adverse reactions with fluticasone furoate and vilanterol were headache and nasopharyngitis. With the exception of pneumonia and fractures, the safety profile was similar in patients with asthma and COPD. During clinical studies, pneumonia and fractures were more frequently observed in patients with COPD.

Tabulated list of adverse reactions

Adverse reactions are listed by system organ class and frequency. The following convention has been used for the classification of frequencies: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

System organ class

Adverse reaction(s)

Frequency

Infections and infestations

Pneumonia*

Upper respiratory tract infection

Bronchitis

Influenza

Candidiasis of mouth and throat

Common

Immune system disorders

Hypersensitivity reactions including anaphylaxis, angioedema, rash, and urticaria.

Rare

Metabolism and nutrition disorders

Hyperglycaemia

Uncommon

Psychiatric disorders

Anxiety

Rare

Nervous system disorders

Headache

Tremor

Very common

Rare

Eye disorders

Vision blurred (see section 4.4)

Uncommon

Cardiac disorders

Extrasystoles

Palpitations

Tachycardia

Uncommon

Rare

Rare

Respiratory, thoracic and mediastinal disorders

Nasopharyngitis

Oropharyngeal pain

Sinusitis

Pharyngitis

Rhinitis

Cough

Dysphonia

Paradoxical bronchospasm

Very common

Common

Rare

Gastrointestinal disorders

Abdominal pain

Common

Musculoskeletal and connective tissue disorders

Arthralgia

Back pain

Fractures**

Muscle spasms

Common

General disorders and administration site conditions

Pyrexia

Common

*, ** See below 'Description of selected adverse reactions'

Description of selected adverse reactions

*Pneumonia (see section 4.4)

In an integrated analysis of the two replicate one year studies in moderate to severe COPD (mean predicted post-bronchodilator screening FEV1 of 45%, standard deviation (SD) 13%) with an exacerbation in the preceding year (n = 3255), the number of pneumonia events per 1000 patient years was 97.9 with FF/VI 184/22 micrograms, 85.7 in the FF/VI 92/22 micrograms and 42.3 in the VI 22 micrograms group. For severe pneumonia the corresponding number of events per 1000 patient years were 33.6, 35.5, and 7.6 respectively, while for serious pneumonia the corresponding events per 1000 patient years were 35.1 for FF/VI 184/22 micrograms, 42.9 with FF/VI 92/22 micrograms, 12.1 with VI 22 micrograms. Finally, the exposure-adjusted cases of fatal pneumonia were 8.8 for FF/VI 184/22 micrograms versus 1.5 for FF/VI 92/22 micrograms and 0 for VI 22 micrograms.

In a placebo-controlled study (SUMMIT) in subjects with moderate COPD (mean percent post-bronchodilator screening FEV1 of 60%, SD 6%), and a history of, or an increased risk of cardiovascular disease, the incidence of pneumonia with FF/VI, FF, VI and placebo was: adverse events (6%, 5%, 4%, 5%); serious adverse events (3%, 4%, 3%, 3%); adjudicated on treatment deaths due to pneumonia (0.3%, 0.2%, 0.1%, 0.2%); the exposure adjusted rates (per 1000 treatment years) were: adverse events (39.5, 42.4, 27.7, 38.4); serious adverse events (22.4, 25.1, 16.4, 22.2); adjudicated on-treatment deaths due to pneumonia (1.8, 1.5, 0.9, 1.4) respectively.

In an integrated analysis of 11 studies in asthma (7,034 patients), the incidence of pneumonia per 1000 patient years was 18.4 for FF/VI 184/22 micrograms versus 9.6 for FF/VI 92/22 micrograms and 8.0 in the placebo group.

**Fractures

In two replicate 12 month studies in a total of 3,255 patients with COPD the incidence of bone fractures overall was low in all treatment groups, with a higher incidence in all Relvar Ellipta groups (2%) compared with the vilanterol 22 micrograms group (<1%). Although there were more fractures in the Relvar Ellipta groups compared with the vilanterol 22 micrograms group, fractures typically associated with corticosteroid use (e.g., spinal compression/thoracolumbar vertebral fractures, hip and acetabular fractures) occurred in <1% of the Relvar Ellipta and vilanterol treatment arms.

For the SUMMIT study, the incidence of all events of fracture with FF/VI, FF, VI and placebo were 2% in each arm; fractures commonly associated with ICS use were less than 1 % in each arm. The exposure-adjusted rates (per 1000 treatment years) for all fracture events were 13.6, 12.8, 13.2, 11.5 respectively; fractures commonly associated with ICS use were 3.4, 3.9, 2.4, 2.1 respectively.

In an integrated analysis of 11 studies in asthma (7,034 patients), the incidence of fractures was <1%, and usually associated with trauma.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms and signs

An overdose of fluticasone furoate/vilanterol may produce signs and symptoms due to the individual component's actions, including those seen with overdose of other beta2-agonists and consistent with the known inhaled corticosteroid class effects (see section 4.4).

Treatment

There is no specific treatment for an overdose with fluticasone furoate/vilanterol. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary.

Cardioselective beta-blockade should only be considered for profound vilanterol overdose effects that are clinically concerning and unresponsive to supportive measures. Cardioselective beta-blocking medicinal products should be used with caution in patients with a history of bronchospasm.

Further management should be as clinically indicated or as recommended by the national poisons centre, where available.